WO2019238068A1 - Sustained-release pregabalin composition and preparation method therefor - Google Patents

Abstract

A sustained-release pregabalin composition, which comprises: (a) an active component, the active component comprising pregabalin or a pharmaceutically acceptable salt or hydrate thereof; (b) a matrix former; (c) a swelling agent; and (d) a gelling agent; and preferably comprises a filler. The sustained-release pregabalin composition, when coming into contact with an aqueous medium, can quickly swell in size beyond the diameter (13 mm) of the pylorus of the human body, and can therefore extend the time before the stomach is emptied so as to increase the time during which pregabalin remains in the stomach, thus increasing the absorption of pregabalin in the small intestine and the ascending colon; at the same time, the sustained-release pregabalin composition implements 24 hour sustained release, thus implementing q.d. (once daily) administration, reducing the number of administrations, and increasing patient compliance.

Description

Sustained-release composition of pregabalin and preparation method thereof

This application claims the priority of a Chinese patent application filed on June 13, 2018 with the Chinese Patent Office, application number 201810608326.0, and the invention name is "a pregabalin sustained-release composition and a method for preparing the same," and October 2018. The priority of a Chinese patent application filed with the Chinese Patent Office on the 16th with an application number of 201811202248.0 and the invention name "a pregabalin sustained-release composition and a method for preparing the same" is incorporated herein by reference in its entirety.

Technical field

The present application belongs to the technical field of pregabalin preparations, and particularly relates to a pregabalin sustained-release composition and a preparation method thereof.

Background technique

Pregabalin is used to treat neuropathic pain and postherpetic neuralgia (PHN) associated with diabetic peripheral neuropathy (DPN). The drug acts as a calcium channel regulator and inhibits the α2-δ subunits of the voltage-dependent calcium channels of the central nervous system. Reducing the influx of calcium ions, and consequently reducing the release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P, thereby effectively controlling neuropathic pain and having anxiolytic and anticonvulsant effects.

Clinical studies have shown that pregabalin is not uniformly absorbed in the gastrointestinal tract. It is well absorbed in the human small intestine and ascending colon, but is rarely absorbed in the intestinal segments outside the colonic hepatic curvature. This means that the average absorption window of pregabalin is about 6 hours or less. Therefore, if pregabalin is made into a conventional sustained-release dosage form, after more than 6 hours, the preparation passes through the colonic hepatic flexure, and the released drug will not be effectively absorbed. Cause waste of drugs. Therefore, how to improve the absorption of pregabalin in the small intestine and the ascending colon has become a technical problem to be solved urgently by those skilled in the art.

Summary of the Invention

The purpose of the embodiments of the present application is to provide a pregabalin sustained-release composition to improve the absorption of pregabalin in the small intestine and the ascending colon. At the same time, the present application also provides a method for preparing the pregabalin sustained-release composition. The specific technical solutions are as follows:

This application first provides a pregabalin sustained-release composition, which comprises:

(a) an active ingredient comprising pregabalin or a pharmaceutically acceptable salt thereof, or a hydrate;

(b) a matrix-forming agent;

(c) swelling agents; and

(d) a gelling agent;

The swelling agent comprises one or at least two of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and polyoxyethylene.

Pregabalin, chemical name: (S) -3-aminomethyl-5-methylhexanoic acid, the chemical structural formula is as follows:

In this application, pregabalin can be prepared as a drug substance by known methods, or it can be obtained through commercial means. No matter what method is used, it is easy for those skilled in the art to implement. Therefore, this application I will not repeat them here. In some specific embodiments of the present application, pregabalin is commercially obtained as a drug substance.

In this application, pregabalin pharmaceutically acceptable salts refer to the addition salts of pharmaceutically acceptable acids and bases; such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, Sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acids (such as acetic acid, HOOC- (CH ₂ ) n-COOH ( Where n 0 to 4)) and so on. Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art are aware of a variety of non-toxic pharmaceutically acceptable addition salts.

In the present application, a hydrate means a molecular complex of a drug (such as pregabalin) and a stoichiometric or non-stoichiometric amount of water.

In some specific embodiments of the present application, the swelling agent may include sodium carboxymethyl starch and include at least one of low-substituted hydroxypropyl cellulose and polyoxyethylene; preferably, the swelling agent includes carboxyl starch. Sodium methyl starch and polyoxyethylene.

In other specific embodiments of the present application, the swelling agent may include at least one of carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, and polyoxyethylene; preferably, the swelling agent includes poly Oxyethylene.

In some specific embodiments of the present application, the particle size range of the pregabalin or a pharmaceutically acceptable salt or hydrate thereof is preferably D ₉₀ 250-600 μm, preferably 300-600 μm, and more preferably 350-500 μm.

In some specific embodiments of the present application, based on the total weight of the pregabalin sustained-release composition, the weight percentage of the active ingredient may be 5% -55%, 5% -50%, 10% -40%. , 10% -35%, 20% -30%, or 25% -30%, etc.

In some specific embodiments of the present application, in addition to pregabalin or a pharmaceutically acceptable salt or hydrate thereof, the active ingredient may optionally include at least one other compound having a synergistic therapeutic effect with pregabalin. Compounds.

In this application, matrix-forming agents are used to provide structural integrity to the composition and help control or prolong the rate of drug release and other functions. Those skilled in the art can select a suitable matrix-forming agent based on the description of the role of the matrix-forming agent herein. In some specific embodiments of the present application, based on the total weight of the pregabalin sustained-release composition, the weight percentage of the matrix-forming agent is 5% -45%, 5% -40%, 15% -35%. Or 15% -30% and so on.

In some embodiments of the present application, the matrix-forming agent may be selected from a mixture of polyvinyl acetate and polyvinylpyrrolidone. Polyvinylpyrrolidone (PVP) is a homopolymer of 1-vinyl-pyrrolidin-2-one, and the molecular weight Mw is usually about 1 × 10 ³ to about 1 × 10 ⁷ , about 2.5 × 10 ³ to about 3 × 10 ⁶ or about 1 × 10 ⁴ to about 1 × 10 ⁵ . Polyvinylpyrrolidone is available from BASF under the trade name

Available from ISP under the trade name

Polyvinyl acetate (PVAc) is a homopolymer of vinyl acetate, and the molecular weight Mw is usually about 1 × 10 ⁵ to about 1 × 10 ⁶ . Based on the total weight of PVAc and PVP, the matrix-forming agent may include PVAc in a weight percentage of 0% -90%, 20% -90%, 60% -90%, 70% -85%. In some embodiments of the present application, the matrix-forming agent is obtained from BASF, and its trade name is

SR, labeled 80/19 (w / w) mixture of PVAc and PVP.

In the present application, the swelling agent can absorb water from the gastric fluid, thereby causing the size of the pregabalin sustained-release composition to swell, and, possibly, the drug release rate can be affected by, for example, creating channels or by forming a hydrocolloid. Swelling agents are soluble in water or insoluble in water. In some specific embodiments of the present application, based on the total weight of the pregabalin sustained-release composition, the weight percentage of the swelling agent may be 5% -70%, 6.5% -70%, 20% -60% , 9% -50%, 20% -30%, 9% -29%, etc. Patent document CN101330907A states that the swelling agent must contain cross-linked polyvinyl pyrrolidone (also known as cross-linked povidone); through a large number of experiments, the inventor unexpectedly found that instead of using cross-linked polyvinyl pyrrolidone, cross-linked carboxyl In the case where one or at least two of sodium methylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and polyoxyethylene are used as swelling agents, Puri can also make Preh The Bahrain sustained-release composition can rapidly expand in volume when exposed to an aqueous medium, and the size of the expansion can reach, or even be better than, the above-mentioned patent. In addition, the inventors also found that the oxides contained in crospovidone have a certain effect on the stability of the composition, and that the formulations containing crospovidone are more hygroscopic and are not conducive to the storage of the formulations.

It should be noted that the swelling agents croscarmellose sodium, calcium carboxymethylcellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and polyoxyethylene used in the present application are commonly used medicines. The auxiliary materials are familiar to those skilled in the art for their structure, properties, and access methods, and are finally used to implement the technical solution of the present application.

In the present application, a gelling agent may alter (eg, prolong) the drug release characteristics of the composition. Gels include synthetic polymers and / or natural polymers that generally have low water solubility (eg, slightly to poorly soluble). When exposed to water, the gel forms a viscous mixture (viscosity greater than water), extending the release of the drug, such as the time for which pregabalin is released from the composition. In some specific embodiments of the present application, based on the total weight of the pregabalin sustained-release composition, the weight percentage of the gelling agent may be 1% -30%, 1% -20%, 3% -20 %, 4% -14% or 3% -10%, etc.

In some specific embodiments of the present application, the gelling agent is selected from one of carbomer, polysaccharide, or a combination thereof. Preferably, the gelling agent is carbomer.

Carbomer is an acrylic polymer bonded to allyl sucrose or pentaerythritol allyl ether. Based on the dry product, the carboxylic acid group (-COOH) is generally 56.0% -68.0%. The average molecular weight of the Carbomer number is about 1 × 10 ⁵ to about 1 × 10 ¹⁰ or about 7 × 10 ⁵ to about 4 × 10 ⁹ .

Polysaccharide (polysaccharide) is a polysaccharide polymer carbohydrate composed of glycoside bond-linked sugar chains, at least more than 10 monosaccharides; in this application, the representative polysaccharides used may include raw gum, inulin, One or a combination of guar gum, chitosan, carob gum, carrageenan.

Xanthan gum, also called corn gum, is a polysaccharide with a molecular weight Mw of about 2 × 10 ⁶ . Inulin, also known as oligofructose and polyfructose, is a class of natural polysaccharides. Generally, the number of D-fructose fragments in inulin ranges from 2 to about 140, and usually ranges from about 25 to about 30. Guar gum is a hydrocolloid polysaccharide having a molecular weight Mw of about 2 × 10 ⁵ . Chitosan is a kind of polysaccharides that are hardly soluble in water. It consists of a copolymer of β-D-glucosamine and N-acetyl-β-D-glucosamine. The number average molecular weight is usually about 1 × 10 ⁴ to about 1 × 10 ⁶ . Carob gum is a natural polysaccharide, similar to guar gum. Carob gum is a galactomannan, and its molecular weight Mw is in the range of about 5 × 10 ⁴ to about 3 × 10 ⁶ . Carrageenan, commonly known as carrageenan, has a chemical structure of calcium, potassium, sodium, and ammonium salts of polysaccharide sulfates composed of galactose and anhydrogalactose. Due to the difference in the sulfate ester binding form, it can be divided into: κ-type, ι-type, λ-type and so on. Carrageenan can be selected in various grades based on gel type, water solubility and viscosity when mixed with water. It should be noted that the above-mentioned polysaccharides are all commercial products, and those skilled in the art can easily obtain and use them to implement the present application.

In some specific embodiments of the present application, the pregabalin sustained-release composition may further include a filler; the filler may change (eg, prolong) the drug release characteristics of the composition, and maintain the rigidity of the tablet during drug release and drug release, The volume and weight of the pregabalin sustained-release composition can also be changed (eg, increased), so as to facilitate subsequent molding of the composition, such as tabletting and the like. Fillers are generally water-soluble and water-insoluble. Water-soluble fillers dissolve to form pores in the framework material to accelerate dissolution; water-insoluble fillers absorb water to swell and accelerate water into the framework material to accelerate dissolution. In the technical solution of the present application, a filler commonly used in the technical field may be selected, including, but not limited to, one of microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium dihydrate dihydrate, and calcium dibasic anhydrous phosphate. Or at least two. In some specific embodiments of the present application, based on the total weight of the pregabalin sustained-release composition, the weight percentage of the filler may be 1% -40%; more specifically, in some embodiments, the filler The weight percentage may be 1% -15% or 3% -8% and the like. In other embodiments, in order to make the filler more significantly change (eg, prolong) the drug release characteristics of the composition and maintain the rigidity of the tablet during drug release and drug release, the weight percentage of the filler is 5%- 40%, more preferably 10-35%, and most preferably 15-30%.

Further, when the swelling agent contains polyoxyethylene and also contains a filler, the pregabalin slow-release composition prepared based thereon has a faster volume expansion rate, especially when the filler contains microcrystalline cellulose, based on this The prepared pregabalin sustained-release composition has a size that swells to more than 13 mm or even 13.5 mm or more after 2 hours of contact with the aqueous medium, and the tablet can maintain good hardness. This result is very amazing and very useful. Those skilled in the art know that the sooner the size swells to 13mm, the more beneficial the pregabalin sustained-release composition stays in the stomach, thereby improving the absorption of pregabalin; and in just 2 hours, the size of the composition When it reaches 13mm, it will be more able to ensure that the pregabalin sustained-release composition is retained in the stomach; the tablet has good hardness, which prolongs the maintenance time of the shape of the tablet, and further guarantees the retention time of the composition in the stomach to achieve sustained release Effect. In this application, the composition "size" corresponds to the longest linear dimension of the cross-section of the dosage form having the smallest area.

In some specific embodiments of the present application, the filler is selected from one or more of microcrystalline cellulose, lactose, and pregelatinized starch. Preferably, the filler is microcrystalline cellulose.

In some specific embodiments of the present application, the pregabalin sustained-release composition may further include a lubricant, which facilitates various processing steps including component mixing, tabletting, and the like; for example, a lubricant may enable pressure distribution during tableting Uniform and make the density of the tablet uniform; the force required to push the tablet out of the die hole is reduced. Another effect that a lubricant may have is to improve the appearance of the tablet and make the surface of the tablet bright and flat. In the technical solution of this application, a lubricant commonly used in the technical field may be selected, including but not limited to magnesium stearate, talc, micronized silica gel, sodium stearyl fumarate, glyceryl behenate, and polyethylene glycol. One or a combination of at least two of them is more preferably magnesium stearate. In some specific embodiments of the present application, based on the total weight of the pregabalin sustained-release composition, the weight percentage of the lubricant may be 0.1% -1.5% or 0.5% -1% and the like.

In some specific embodiments of the present application, the pregabalin sustained-release composition may further include a coating powder. In the technical solution of the present application, a coating powder commonly used in the technical field may be selected, including but not limited to polyvinyl alcohol And at least one of polyethylene glycol, at least one of silica and talc, and / or flavoring agent; in some specific embodiments of the present application, based on the pregabalin sustained-release composition The total weight of the coating powder may be 2% to 6%, 3% to 4%, and the like.

The application also provides a method for preparing the above-mentioned pregabalin sustained-release composition, which includes:

The active ingredients, matrix former, swelling agent and gelling agent, and optional fillers are mixed and then shaped. In a specific implementation process, the forming process may include granulation, optionally granulation, and tabletting steps. In this application, the particle size D _{90 of the} pregabalin drug substance can be controlled to 250-600 μm, more preferably 300 to 600 μm, and more preferably 350 to 500 μm, and a matrix forming agent, a swelling agent, and a coagulant with good fluidity can be selected. Adhesive, which realizes that the sustained-release tablets can be prepared by direct compression in the process. In some embodiments, other pregabalin APIs with controlled particle size ranges can also be used, such as pregabalin APIs with D ₅₀ of 50-200 μm, and pregabalin APIs with D ₅₀ of 50-175 μm. It should be noted that the mixing and subsequent molding steps are conventional steps and operations in the technical field to which they belong, and are not specifically limited herein.

In addition, in the process of preparing the pregabalin sustained-release composition, the inventors investigated the effect of the mixing time on the uniformity of the content of the mixed material; it was found that the longer the mixing time within 20 minutes, the better the content uniformity. After 20 minutes, the content uniformity has no obvious change or even worsens. The specific test results are shown in Table 1. Based on this, in some specific embodiments of the present application, the mixing time in the mixing process is 10-30 minutes, preferably 10-25 minutes, more preferably 15 minutes, and most preferably 20 minutes. It should be noted that the mixed material referred to herein includes an active ingredient, a matrix-forming agent, a swelling agent, a gelling agent, and optionally a filler.

Table 1

In some embodiments of the present application, when the pregabalin sustained-release composition contains a lubricant, the active ingredient, matrix-forming agent, swelling agent, gelling agent, and optionally filler can be mixed, and then

A: It is mixed with all the lubricants, and then the molding process is performed;

or

B: It is mixed with a part of the lubricant, and then granulated and optionally granulated, and then the remaining part of the lubricant is added, and then other forming processes are performed, such as tabletting.

In some specific embodiments of the present application, when the pregabalin sustained-release composition contains a coating powder, the preparation method further includes: after forming, using a film coating premix to perform a coating process. The film coating premix may include at least one of polyvinyl alcohol and polyethylene glycol, at least one of silica and talc, and / or a flavoring agent. The content may be 10% to 25%, and the solid content of the further film coating premix may be 10% to 15%. It should be noted that the coating process is also a conventional process and operation in the technical field, and is not specifically limited herein.

The pregabalin sustained-release composition provided in the present application can be made into a tablet form. Based on this, the present application also provides a pregabalin sustained-release tablet, which comprises the aforementioned pregabalin sustained-release composition.

The pregabalin slow-release composition provided by the present application can rapidly expand in volume when exposed to an aqueous medium, exceeding the diameter of the human gastric pylorus (13mm), and therefore can prolong gastric emptying time to increase the residence time of pregabalin in the stomach and improve The absorption of pregabalin in the small intestine and the ascending colon is achieved; meanwhile, the pregabalin sustained-release composition provided by the present application achieves a slow release for 24 hours, which can realize QD (once a day) administration, reduce the number of medications, and improve the patient Compliance.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to more clearly illustrate the embodiments of the present application and the technical solutions of the prior art, the following briefly introduces the embodiments and the drawings needed in the prior art. Obviously, the drawings in the following description are only the present invention. Some embodiments of the application, for those of ordinary skill in the art, can obtain other drawings according to these drawings without paying creative labor.

FIG. 1 is a dissolution curve of Examples 1-8 and Comparative Example 1 of this application;

FIG. 2 shows examples 10-17 and reference preparations of the present application.

Dissolution profile

Figure 3 shows a single oral pregabalin sustained-release tablet test preparation (330mg / tablet) and a reference preparation after a meal.

(330 mg / tablet) mean drug concentration-time curve of pregabalin in plasma (Mean ± SD).

detailed description

In order to make the technical problems, technical solutions, and beneficial effects solved by this application clearer, the following further describes this application in combination with specific embodiments. In the following examples, unless otherwise stated, the specific conditions of the test methods are generally implemented in accordance with conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents are all obtained from the market or prepared using public information.

Preparation examples of pregabalin sustained-release tablets (oval tablets)

The English abbreviations appearing in the following examples are shown in Table 2 below:

Table 2

Example 1

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

CMS-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 2

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

Pass 40 mesh sieve together with Carbomer 974P, then add PEO, mix for 10min with mixer, add half of the prescribed amount of magnesium stearate and mix for 5min, dry granulate. After granulating through 20 mesh sieve, add half of the prescribed amount of hard Magnesium stearate was mixed for 10 min and compressed.

Example 3

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

CMS-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 4

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

CMS-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 5

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

CC-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 6

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

L-HPC and carbomer 974P were passed through a 40-mesh sieve, and then PEO was added, mixed by a mixer for 15 minutes, and mixed with magnesium stearate for 5 minutes, and compressed.

Example 7

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

L-HPC and chitosan were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 8

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

CMS-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted. It was also coated with a film coating premix with a solid content of 12% (w / w), and the coating weight was increased to 3%. The film coating premix contains polyvinyl alcohol, silica, talc, polyethylene glycol and flavoring agent; it is obtained by dissolving the above materials in purified water and passing through a 80 mesh sieve.

Example 9

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

Microcrystalline cellulose and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 10

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

CMS-Na and carbomer pass through a 18 mesh sieve together, then add PEO, mix with a mixer for 15min, add magnesium stearate and mix for 5min, and tablet.

Example 11

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

Carboxymethylcellulose calcium and carbomer are passed through a 18 mesh sieve together, then added with PEO, mixed with a mixer for 10 minutes, mixed with a prescribed amount of magnesium stearate and mixed for 5 min, granulated by dry method, sized through a 20 mesh sieve, and then added Half of the prescribed amount of magnesium stearate was mixed for 10 minutes and compressed into tablets.

Example 12

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

L-HPC and carbomer pass through a 18 mesh sieve together, then add PEO, mix with a mixer for 15min, add magnesium stearate and mix for 5min, and tablet.

Example 13

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

The microcrystalline cellulose and carbomer were passed through an 18 mesh sieve together, and then PEO was added, and the mixer was mixed for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 14

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

CC-Na and Carbomer were passed through an 18 mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 15

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

Pregelatinized starch and carbomer passed through an 18 mesh sieve together, then added PEO, mixed with a mixer for 20 minutes, added magnesium stearate and mixed for 5 minutes, and pressed into tablets.

Example 16

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

The microcrystalline cellulose and carbomer were passed through an 18 mesh sieve together, and then PEO was added, and the mixer was mixed for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.

Example 17

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

The microcrystalline cellulose and carbomer are passed through a 18 mesh sieve together, then PEO is added, and the mixer is mixed for 20 minutes, and magnesium stearate is added for 5 minutes, and compressed. It was also coated with a film coating premix with a solid content of 20% (w / w), and the weight of the coating was increased to 3%. The film coating premix contains polyvinyl alcohol, silica, talc, polyethylene glycol and flavoring agent; it is obtained by dissolving the above materials in purified water and passing through a 80 mesh sieve.

Examples 18-26

Refer to the preparation method of Example 8 and the prescription in Table 3 below to complete Examples 18-26.

table 3

Examples 27-34

With reference to the preparation method of Example 17, and the prescription in Table 4 below, Examples 27-34 are completed.

Table 4

Comparative Example 1

Example 30 in patent CN101330907A

Comparative Example 2

prescription:

Preparation method: Weigh the prescribed amount of pregabalin and

Pass through a 40-mesh sieve together, add PEO, mix with a mixer for 15min, add magnesium stearate and mix for 5min, and tablet.

Comparative Example 3

prescription:

Preparation method: Weigh out the prescribed amounts of pregabalin and PEO, mix with a mixer for 15min, add magnesium stearate and mix for 5min, and tablet.

Comparative Example 4

prescription:

Preparation method: Weigh the prescribed amount of pregabalin,

Pass the 40 mesh sieve together with Carbomer 974P, mix for 10 minutes with a mixer, add half of the prescribed amount of magnesium stearate and mix for 5 minutes, dry granulate. After granulating through a 20 mesh sieve, add half of the prescribed amount of magnesium stearate and mix. 10min, compressed.

Drug dissolution and swelling test

Test one

Tablet dissolution test of Examples 1-8 and Comparative Example 1

1. Dissolution method:

1) Method: Dissolution measurement method (the second method of the "General Pharmacopoeia 2015 Edition" 0931 Dissolution and Release Measurement Method ", second method (paddle method), plus sedimentation basket).

2) Dissolution medium: 0.06mol / L HCl, 900ml

3) Speed: 50 rpm

4) Sampling time: 1h, 2h, 4h, 6h, 9h, 12h, 16h, 24h

5) Detection method: high performance liquid chromatography, detection wavelength: 210nm

6) Preparation of test solution: Take 10ml of solution at each time point and filter.

7) Preparation of reference solution: take pregabalin reference solution and use 0.06mol / L HCl to prepare a reference solution solution with a concentration of about 360 μg / ml.

2. Instrument model:

Intelligent Dissolution Tester (Model: DT820, Manufacturer: German Iveka Co., Ltd.)

3. Dissolution results

The dissolution results of Example 1-8 and Comparative Example 1 in 0.06mol / L HCl medium are shown in Table 5 and Figure 1:

table 5

lot number	1h	2h	4h	6h	9h	12h	16h	24h	f 2
Comparative Example 1	18.4	28.6	44.0	55.8	69.1	79.6	90.2	100.4	NA

Example 1	17.3	27.1	41.3	52.4	64.8	74.3	83.5	96.5	69
Example 2	18.0	27.2	39.7	48.9	59.2	67.4	77.5	90.9	54
Example 3	17.8	27.1	40.9	51.7	64.1	73.7	83.4	95.8	67
Example 4	16.2	25.7	39.8	51.4	65.1	75.7	86.1	97.1	69
Example 5	19.8	29.8	41.1	53.4	65.2	76.4	86	99.7	74
Example 6	15.7	25.8	38.1	51.0	63.1	72.4	84.1	97.1	64
Example 7	15.9	25.8	36.5	48.5	61.1	73.1	81.4	94.2	58
Example 8	16.4	28.1	37.4	51.2	63.4	75.7	85.1	100.7	65

Note: The dissolution results in the table are in percentage.

It can be seen from Table 5 and Figure 1 that the pregabalin sustained-release tablets prepared in Examples 1-8 of the present application are slowly released within 24 hours, released less than 30% within 2 hours, 60% -80% released after 12 hours, and released substantially within 24 hours. ; Its dissolution characteristics are basically consistent with the dissolution performance of the sustained-release tablet (Comparative Example 1) described in the patent CN101330907A, and QD administration can be achieved.

Test two

Measurement of swelling size of tablets of Examples 1-8 and Comparative Examples 1-4:

According to the second method ("paddle method" of the "0931 Dissolution and Release Determination Method") of the fourth part of the general guideline of the 2015 edition of the Chinese Pharmacopoeia, dissolution experiments were performed on the tablets prepared in the above examples. 900ml 0.06N HCl solution was used as the dissolution medium, and the rotation speed was 50 rpm. The drugs were taken out of the dissolution medium at 1h, 2h, and 6h in the dissolution experiment, and the size was measured with an electronic vernier caliper. Compared with the tablet (the tablet before the experiment) at 0h, the results are shown in Table 6 below:

Table 6

Note: The swell of the sample of Comparative Example 2 increases first, and then with the swelling time, the tablet becomes soft, the mechanical strength is poor, and the thickness of the tablet becomes low. After taking out, the sample slumps on the experimental table. Film length, width and thickness.

It can be seen from Table 6 that the swelling size of the tablets prepared in Examples 1, 3, 4, and 8 of this application after 2 hours has reached 13 mm or more (this size corresponds to the longest linear size of the cross-section of the dosage form with the smallest area), Significantly better than Comparative Example 1; after 6 hours of other examples, the swelling size also reached more than 13mm; this size can effectively delay the residence time of the sustained-release tablet in the stomach, and stay in the stomach after mechanical retardation. At the same time, the pharmaceutical composition can continuously release pregabalin, effectively widen the pregabalin's absorption window, and improve the absorption of pregabalin in the small intestine and ascending colon to allow QD administration. Moreover, compared with Comparative Examples 2-4, it can be seen that in the absence of at least one of matrix-forming substance, swelling agent, and gelling agent, the swelling size is smaller than that of Example 1-8.

Test three

Examples 10-17 and reference preparations

Dissolution test

For the dissolution method, refer to Test 1. The sampling time is: 1h, 2h, 4h, 6h, 8h, 10h, 12h, 16h, 24h. Intelligent dissolution tester is the same as test one;

Examples 10-17 and reference preparations in 0.06mol / L HCl medium

The dissolution results are shown in Table 7 and Figure 2:

Table 7

Note: The dissolution results in the table are all percentages.

It can be seen from Table 7 and FIG. 2 that the pregabalin sustained-release tablets prepared in Examples 10-17 of the present application are slowly released within 24 hours, released <25% within 1 hour, released more than 60% within 8 hours, and substantially released 100% within 24 hours; Its dissolution characteristics and the sustained-release tablets of Comparative Example 1 and

The dissolution performance is basically the same, and QD administration can be achieved.

Test four

Examples 10-17 and

Determination of swelling size of tablets:

Refer to Test 2 for the determination method. The results are shown in Table 8 below:

Table 8

Note: The sample of Example 11 was dispersed for 1 hour and the size could not be determined.

It can be seen from Table 8 that the swelling size of the tablets prepared in the examples of the present application has reached 13 mm and above after 2 h (this size corresponds to the longest linear size of the cross-section of the dosage form with the smallest area).

Similar (the difference in the initial film size in this study was due to the difference in film type), and the increase in film thickness was greater than that in the comparative example and

Tablet. This size can effectively delay the residence time of the sustained-release tablet in the stomach through mechanical block. When staying in the stomach, the pharmaceutical composition can continuously release pregabalin, effectively widening the pregabalin's absorption window. Increases the absorption of pregabalin in the small and ascending colons and allows QD administration.

Drug rigidity measurement

Examples 10-16 and

Dissolution test of tablets

1. Determination method:

According to the second method ("paddle method" of "0931 Dissolution and Release Determination Method") of the fourth part of the General Edition of the Chinese Pharmacopoeia 2015, add a sedimentation basket to perform the dissolution test on the tablets prepared in Examples 10 to 16, using 900ml 0.06mol / The LHCl solution was used as the dissolution medium, and the dissolution test was performed at 37 ± 5 ° C and a paddle speed of 50 rpm. The drug was taken out of the medium at 2h, 6h and 24h after the test was started, and the sample rigidity measurement was performed under the following set conditions. The test results are shown in Table 9.

Instrument: Texture Tester (EZ Test)

Load unit: 5kg

Probe: 1/4 ball probe

Triggering force: 0.5g

Test speed: 0.2m / s

Acquisition rate: 10 points / second

Test distance: 8 ～ 10mm

Table 9

It can be seen from Table 9 that the tablets prepared in Examples 10, 11, 12 and 14 of the present application are more rigid after 2h, 6h and 24h.

The tablets were inferior, while the fillers of Examples 13, 15 and 16 had significantly increased rigidity, which was significantly better than

Tablet. The rigidity of the drug in the dissolution process can prevent the drug from being damaged by the gastrointestinal food, thereby extending the residence time of the drug in the stomach and widening the absorption window. Increased pregabalin absorption in the small and ascending colons allows QD administration. It is known from the measurement result that the use of the filler of the present application effectively improves the rigidity of the preparation, maintains the shape of the drug, and ensures the continuous release of the drug.

Drug stability test

Example 17 and reference preparation

After examining the influencing factors, the appearance characteristics, weight loss, dissolution, content, and related substances of the 30-day samples are shown in Tables 10 to 14:

Table 10 Inspection results of appearance characteristics

Note: "-" means not inspected.

Table 11 Results of weight gain investigation

Note: "-" means not inspected.

Table 12 Dissolution inspection results

Table 13 Investigation results of related substances

Note: Impurity C is a degradation impurity of active substance pregabalin, molecular formula C8H15NO, molecular weight 141.21, name: 4-isobutylpyrrolidin-2-one The structural formula is as follows:

Table 14 Content inspection results

The test results of influencing factors indicate that the samples were left for 30 days under each condition.

There were no significant changes in appearance. Pregabalin sustained-release tablets have a certain hygroscopicity. Under high humidity (RH 75%), the moisture absorption and weight gain of Example 17

Low, that is, the hygroscopicity of Example 17 is relatively

Significant improvement. There was no significant change in dissolution under all conditions. The dissolution curves of Example 17 were the same.

similar. The degradation of impurity C in pregabalin sustained-release tablets has increased under high temperature conditions.

remarkable growth,

The increase is more obvious, that is, the stability of Example 17 is better.

In summary, the stability results show that the stability of the homemade Example 17 tablet is significantly better than

In vivo bioequivalence test

Experimental purpose

A single oral pregabalin extended-release reference formulation (R,

Sustained-release tablets, batch number T73417, specification 330mg / tablet) and test preparation (T, Example 17, specification 330mg / tablet), the bioequivalence of the two preparations was evaluated.

2.Instruments, medicines and reagents

2.1 Equipment

name	Manufacturer / Model	equipment number
Balance	Germany Sartorius / MSA225S-CE	Ⅱ051-021
Vortex mixer	Wiggens Vortex 300	Ⅱ050-477
Multi-tube Vortex Oscillator	Beijing Tajin Technology Co., Ltd. VX-Ⅱ	Ⅱ050-490
Desktop high-speed refrigerated centrifuge	Sigma 3K15	Ⅱ050-494
Desktop high-speed refrigerated centrifuge	Sigma 3-18KS	Ⅱ050-693
UPLC-MS / MS	Waters ACQUITY UPLC H-class / XEVO TQD	Ⅱ050-503
Milli Q ultra pure water meter	MilliporeAdvantage A10	Ⅱ050-325

2.2 Drugs and reagents

3. Sample processing

Take 40 μL of unknown plasma sample, add 40 μL of acetonitrile-water solution (1: 1, v / v), add 40 μL of internal standard solution (pregabalin-d4 1000ng · mL ^-1 ), then add 120 μL of methanol, vortex for 2 min, and 15000 rpm Centrifuge at 4 ° C for 10 min. Take 50 μL of the supernatant and add 150 μL of 0.1% formic acid in water to mix. Take 5 μL for quantitative analysis by LC-MS / MS.

4. Experimental results

4.1 Human plasma sample test

The human plasma samples to be tested are divided into 6 batches for analysis, and the linear correlation coefficient of all analysis batches is greater than 0.9900. The average RE% of each concentration point on the standard curve of different batches of pregabalin sustained-release tablets was within ± 15%. The plasma drug concentration time curve of the test preparation and the reference preparation of a single oral pregabalin sustained-release tablet after a meal in healthy subjects is shown in FIG. 3.

4.2 Pharmacokinetic parameters of human plasma

After taking a single meal of HPR test preparations and reference preparations in healthy subjects, the average elimination half-life of HPR compared to the test preparations and reference preparations was _1/2 , 6.08 ± 0.718h and 6.08 ± 1.05h, respectively. The average peak time T _max is 8.80 ± 3.08h and 9.90 ± 3.35h, the average C _max is 4381 ± 1107ng · mL ^-1 and 4370 ± 870ng · mL ^-1 , and the average AUC _{0 → t} is 71361 ± 12040h · ng · mL ^-1 and 72243 ± 17132h · ng · mL ^-1 , the average AUC _{0 → ∞} were 72053 ± 12163h · ng · mL ^-1 and 73131 ± 17371h · ng · mL ^{-1, respectively} .

4.3 Human plasma statistics

The 90% confidence intervals of the ratios of Ln (AUC _{0 → t} ), Ln (AUC _{0 → ∞} ), and Ln (C _max ) of the two preparations fall between 90.72% ～ 111.45%, 90.39% ～ 111.29%, and 88.54% ～ 110.80%, respectively. Within the range, T _max P value <0.05 by two-sided t test. The above results show that the two formulations are bioequivalent. Table 15 shows the statistical results of the bioequivalence confidence intervals for healthy people after oral administration of test preparation and reference preparation after a single meal.

Table 15

Note: AUC _{0 → t} , AUC _{0 → ∞,} and C _max 90% confidence interval equivalent criterion: 80.00% ～ 125.00%; T _max equivalent criterion: p≥0.05

The role of the foregoing embodiments is to explain the substance of the present application, but not to limit the scope of protection of the present application. Those of ordinary skill in the art should understand that the technical solutions of the present application can be modified or equivalently replaced without departing from the essence and scope of protection of the technical solutions of the present application.

Claims (14)

1. A pregabalin sustained-release composition, comprising:

   (a) an active ingredient comprising pregabalin or a pharmaceutically acceptable salt thereof, or a hydrate;

   (b) a matrix-forming agent;

   (c) swelling agents; and

   (d) a gelling agent;

   The swelling agent comprises one or at least two of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and polyoxyethylene.
2. The pregabalin sustained-release composition according to claim 1, wherein the swelling agent comprises sodium carboxymethyl starch, and comprises at least one of low-substituted hydroxypropyl cellulose and polyoxyethylene; preferably, all The swelling agent comprises sodium carboxymethyl starch and polyoxyethylene.
3. The pregabalin sustained-release composition according to claim 1, wherein the swelling agent comprises at least one of calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and polyoxyethylene; preferably, the swelling agent The swelling agent contains polyoxyethylene.
4. The pregabalin sustained-release composition according to any one of claims 1-3, wherein the pregabalin or a pharmaceutically acceptable salt or hydrate thereof preferably has a particle diameter range of D ₉₀ 250 to 600 μm, It is preferably 300 to 600 μm, and more preferably 350 to 500 μm.
5. The pregabalin sustained-release composition according to any one of claims 1-4, wherein the composition further comprises a filler, and the filler is preferably microcrystalline cellulose, lactose, starch, pregelatinized starch One or at least two of calcium phosphate dihydrate and anhydrous calcium hydrogen phosphate; more preferably, the filler comprises one or at least two of microcrystalline cellulose, lactose, and pregelatinized starch, most Preferably, the filler is microcrystalline cellulose.
6. The pregabalin sustained-release composition according to claim 5, wherein the weight percentage of the filler is 1% to 40% based on the total weight of the pregabalin sustained-release composition;

   Preferably, the weight percentage of the filler is 1% to 15%, more preferably 3% to 8%;

   Or preferably, the weight percentage of the filler is 5% to 40%, more preferably 10 to 35%, and most preferably 15% to 30%.
7. The pregabalin sustained-release composition according to any one of claims 1-6, wherein the matrix-forming agent is selected from a mixture of polyvinyl acetate and polyvinylpyrrolidone.
8. The pregabalin sustained-release composition according to any one of claims 1 to 7, wherein the gelling agent is selected from one of carbomer, polysaccharide, or a combination thereof, and preferably the gelling agent For Capom.
9. The pregabalin sustained-release composition according to any one of claims 1-8, wherein based on the total weight of the pregabalin sustained-release composition:

   The weight percentage of the active ingredient is 5% -55%, preferably 5% -50%, more preferably 10% -40%, and still more preferably 10% -35%;

   The weight percentage of the matrix forming agent is 5% to 45%, preferably 5% to 40%, and more preferably 15% to 35%;

   The weight percentage of the swelling agent is 5% -70%, preferably 6.5% -70%, and further preferably 20% -60%, 9% -50%, or 9% -29%;

   The weight percentage of the gelling agent is 1% -30%, preferably 3% -20%, and more preferably 3% -10%.
10. The pregabalin sustained-release composition according to any one of claims 1-9, wherein the composition further comprises a lubricant, and the lubricant is preferably magnesium stearate, talc, micronized silica gel, stearin One or at least two of sodium fumarate, glyceryl behenate and polyethylene glycol, more preferably magnesium stearate; also preferably, based on the total weight of the pregabalin sustained-release composition, The weight percentage of the lubricant is 0.1% -1.5%, preferably 0.5% -1%.
11. The pregabalin sustained-release composition according to any one of claims 1 to 10, wherein the composition further comprises a coating powder, preferably, the coating powder comprises polyvinyl alcohol and polyethylene glycol At least one of silica, talc, and / or flavoring agent; more preferably, the weight percentage of the coating powder based on the total weight of the pregabalin sustained-release composition It is 2% to 6%, preferably 3% to 4%.
12. The method for preparing a pregabalin sustained-release composition according to any one of claims 1-11, comprising:

    The active ingredients, matrix-forming agent, swelling agent, gelling agent, and optional filler are mixed and then subjected to a molding process.
13. The method for preparing a pregabalin sustained-release composition according to claim 12, wherein the mixing time is 10-30 minutes, preferably 10-25 minutes, more preferably 15 minutes, and most preferably 20 minutes.
14. A pregabalin sustained-release tablet comprising the pregabalin sustained-release composition according to any one of claims 1-11.

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